Contents

The American Academy of Sleep Medicine (AASM) recommends sodium oxybate as a standard of care for the treatment of cataplexy, daytime sleepiness, and disrupted sleep due to narcolepsy in its Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin,[5] and the drug has been safely used by patients with narcolepsy for more than seven years.[6] A recent analysis evaluated the postmarketing safety of sodium oxybate (Wang et al. 2009), including rates of abuse, dependence, and withdrawal, using a conservative application of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria to all worldwide sodium oxybate adverse event cases containing reporting terminology related to abuse or misuse.[6] The analysis included cases reported to the manufacture from market introduction in 2002 through March 2008. Using the DSM-IV criteria, the analysis found the following rates of abuse, dependence, and withdrawal of the approximately 26,000 patients who used sodium oxybate during this period:

The analysis also found 2 confirmed cases (0.008%) of sodium oxybate–facilitated sexual assault; in both cases the women knew that they were taking sodium oxybate. In addition, there were 21 deaths (0.08%) in patients receiving sodium oxybate treatment, with 1 death known to be related to sodium oxybate, and 3 cases (0.01%) of traffic accidents involving drivers taking sodium oxybate. The extremely low rates of abuse, dependence, withdrawal, and assault found in this analysis suggest that after seven years of commercial availability, sodium oxybate use is largely appropriate and confined to patients with legitimate therapeutic needs.[6]

On October 18, 2011, Jazz Pharmaceuticals, Inc. disclosed that it had received a Warning Letter from the FDA for specific violations during the FDA's inspection of the firm from April 27, 2011 through May 6, 2011.[9] In the letter the FDA cited 2 specific violations: 1. Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA [21 C.F.R § 314.80(b)]. 2. Failure to submit adverse drug experience (ADE) reports that are both serious and unexpected to FDA within 15 calendar days of initial receipt of the information by the applicant [21 C.F.R. § 314.80(c)(1)(i)]. The firm also received an FDA form 483 on September 27, 2007, for similar post-marketing safety violations.[9]

Sodium oxybate is generally well tolerated by most patients. The most common side effects reported in clinical trials include nausea, dizziness, headache, vomiting, sleepiness, and bed-wetting.[10][11] Some patients treated with sodium oxybate have also experienced moderate to significant weight loss. This may be due to the fact that sodium oxybate improves sleep architecture and increases the length of deep sleep stages, resulting in increased production of human growth hormone (HGH) and changes in energy metabolism.[12] The weight loss could also be due to decreased daytime appetite (experienced by many users) and the instructions to not eat for two hours before bedtime. Serious side effects, as listed on all prescriptions of sodium oxybate, can include hallucinations, agitation, severe mental confusion, abnormal thinking, disrupted sleep, and depression.

The U.S. Food and Drug Administration categorizes sodium oxybate as Pregnancy Category C for all trimesters of pregnancy. [13][14] Currently, there are no well-controlled studies in pregnant women. Animal studies have shown adverse effects on the fetus. In one study, rats were given oral sodium oxybate throughout pregnancy and lactation. This resulted in increased stillbirths, decreased offspring survival after birth, and decreased body weight gain.[13] In another study, pregnant rats and pregnant rabbits were given oral sodium oxybate during organogenesis. This resulted in no evidence of adverse effects on fetal development.[13] As such, sodium oxybate should be used in pregnancy only if the benefit outweighs the risk for the fetus.

Sodium oxybate is designated as an orphan drug, a pharmaceutical drug developed specifically to treat an orphan disease.[16] The development of sodium oxybate oral solution as a prescription medication was initiated by the Office of Orphan Products Development (OOPD),[17] a department of the FDA dedicated to promoting the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.[18]

In 1994, the OOPD petitioned a pharmaceutical company called Orphan Medical to investigate sodium oxybate as a potential treatment for narcolepsy.[17]

In 2000, Orphan Medical submitted a New Drug Application (NDA) to the FDA for sodium oxybate.[17] Sodium oxybate was granted "Priority Review",[17] which is an expedited review process given to products that offer a major advance in treatment or treatment where no adequate therapy exists.[19]

In 2002, sodium oxybate received approval from the FDA for the treatment of cataplexy in patients with narcolepsy.[2]

In 2005, the Xyrem brand was acquired by Jazz Pharmaceuticals when they purchased Orphan Medical. Later that year, sodium oxybate was granted a second indication by the FDA for the treatment of EDS in patients with narcolepsy.[1] Also that year sodium oxybate was approved for the treatment of cataplexy in patients with narcolepsy by Health Canada's Therapeutic Products Directorate,[3] and for the same indication in adult patients by the European Medicines Agency for the European Union (EU) and the Swiss Agency for Therapeutic Products, Swissmedic.[6]

In 2006, sodium oxybate received an expanded indication for narcolepsy with cataplexy in the EU.[6]

Orphan drugs by their nature are very specialized and have relatively few patients to spread the costs associated with bringing them to market. The average cost of a specialty drug in the US was $65,000 annually in June 2013 (about $5,416 a month). The price of Xyrem in the US has inflated by an average of 40% annually since it became available as a prescription.[25]

In European Union (EU) countries, the government either provides national health insurance (as in the UK and Italy) or strictly regulates quasi-private social insurance funds (as in Germany, France, and the Netherlands). These government agencies are the sole purchaser (or regulator) of medical goods and services and have the power to set prices.[26] The cost of pharmaceuticals, including sodium oxybate, tends to be lower in these countries.[26]

In the US, the cost of Xyrem is $4,032.30 per 180 mL bottle (500 mg/mL)(typically a 10 day supply), compared to $576.00 (£360) in the UK under the NHS.[citation needed] The dose range is 4.5–9 grams per night (with a therapeutic dose range of 6-9 grams per night), which equates to $6,048.60 (4.5g) to $12,097.20 (9g) per month as of February 2014; Jazz Pharmaceuticals increases its prices for Xyrem on a semi-annual basis. Xyrem is covered by most insurance plans including Medicare and Medicaid and approximately 90% of Xyrem patients have a flat monthly co-pay. 75% of Xyrem insurance copays are less than $50 and 42% are less than $25 for a one-month supply. The manufacturer offers a coupon program for patients with larger co-pays. Some insurance companies may require physicians to fill out an insurance form called a Prior Authorization as part of the prescribing process. Additionally, the manufacturer offers a Patient Assistance Program to patients that do not have insurance and are unable to afford their Xyrem prescription. Approximately 8% of Xyrem patients currently participate in this program and receive their prescription for free.[27]

Existing US Patents on sodium oxybate prevent other companies from manufacturing it as a drug. Sodium oxybate is protected by US Patents 6472431,[28] and 6780889[29] In total, sodium oxybate is protected by eight patents related to the product's formulation and Jazz Pharmaceuticals' distribution system. These patents expire from 2019 to 2024.[30]

A number of measures have been put in place by sodium oxybate's manufacturers to ensure that it is used safely and appropriately. For example, in the US sodium oxybate requires a prescription and can only be obtained through a restricted distribution program, called the "Xyrem Success Program". This restricted distribution program is required by the FDA as part of a Risk Management Program (RMP) to manage product safety and prevent abuse.[31]

The program involves many risk management components, such as:

Physician education

Registration

Patient education

Detailed patient surveillance

The program includes a single centralized pharmacy with a toll-free number.

Initial dosages are set by the prescribing physician. Each bottle of sodium oxybate is shipped with a graduated syringe (measured in grams) and two dosing cups. Each night, the patient mixes two doses with 60 ml of water (sometimes substituted with a calorie-free beverage to cover the unpleasant taste of the medication). The first dose is taken at bedtime, and the second is taken 2.5 to 4 hours later.